Thiophene-1,1-dioxides

ABSTRACT

3-AMINO-2,4-DIARYL-THIOPHENE-1,1-DIOXIDES, E.G. THOSE OF THE FORMULA   1,1-DI(O=),2-R2,3-R1,4-(AM-),5-R3-THIOPHENE   AM=TERT. AMINO R2=H OR ALKYL   ARE ANTIPARASITIC AGENTS.

United States Patent 3,706,769 THIOPHENE-1,1-DIOXIDES Melvin HarrisRosen, Florham Park, and Herbert Morton Blatter, Summit, N.J., assignorsto Ciba-Geigy Corporation, Ardsley, N.Y.

No Drawing. Continuation-impart of application Ser. No. 765,974, Oct. 8,1968. This application June 8, 1970, Ser. No. 44,553

Int. Cl. A61k 27/00; C07d 63/12 U.S. Cl. 260332.1 Claims ABSTRACT OF THEDISCLOSURE 3-amino-2,4- diaryl-thiophene-1,1-dioxides, e.g. those of theformula R1 Am R1] [R3 8 Am=tert. amino R =H or alkyl are antiparasiticagents.

are antiparasitic agents.

CROSS-REFERENCE TO RELATED APPLICATION This is a continuation-in-part ofapplication Ser. No. 765,974, filed Oct. 8, 1968 now U.S. Patent No.3,629,437.

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new 3-amino-2,4-diaryl-thiophene-1,1- dioxides,more particularly of those of the Formula I in which Am is a tertiaryamino group, R is hydrogen or lower alkyl and each of R and R is anisoor heterocyclic aryl radical, of corresponding pharmaceutical orveterinary compositions, feedstutfs or additives thereof and of methodsfor the preparation and application of these products. Said compositionsor feedstuifs alone, or

in combination with other therapeutic agents, are useful antiparasitic,preferably coccidiostatic agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The tertiary amino group Amrepresents preferably dilower alkylamino, e.g. dimethylamino,N-methyl-N-ethylamino, diethylamino, di-n-propylamino, di-isopropylaminoor d-n-butylamino, but also, for example, lower alkyleneimino ormonooxa-, monothiaor monoaza-lower alkyleneimino, e.g. ethyleneimino,pyrrolidino, Z-methylpyrrolidino, piperidino, 2- or 4-methyl-piperidino,1,6- or 2,5 hexamethyleneimino, 1,7- or 2,6 heptamethyleneimino;morpholino, 3-methyl-morpholino or thiamorpholino; piperazino, 4-(methyl, ethyl, n-propyl or i-propyl)-piperazino, 3-(methyl, ethyl orn-propyl)-3-aza-1,5- or 1,6-hexy1eneimino or 4-methyl-4-aza-1,7- or2,6-heptyleneimino. In the above amino groups two heteroatoms areseparated by at least 2 carbon atoms, and the term lower referred toabove and hereinafter in connection with orgame radicals or compoundsrespectively, defines such with up to 7, preferably up to 4, carbonatoms.

A lower alkyl group R is preferably methyl, but also, for example,ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or -heptyl.

Patented Dec. 19, 1972 The iso or heterocyclic aryl radicals R and Rrepresent preferably monocyclic isocyclic or monooxa-, monothiaormonoaza-cyclic aryl radicals, which are unsubstituted or substituted byone or more than one, preferably by 1 or 2, of the same or of differentsubstituents, for example, by lower alkyl, such as methyl, ethyl, nori-propyl or -butyl, free, etherified or esterified hydroxy or mercaptogroups, such as lower alkoxy or alkylmercapto, e.g. methoxy, ethoxy, nori-propoxy or -butoxy, halo, e.g. iluoro, chloro or bromo,trifluoromethyl, nitro or amino, especially dilower alkylamino, e.g.dimethylamino or diethylamino. Preferred aryl radicals are phenyl,(lower alkyl)-phenyl, (lower alkoxy)-phenyl, (loweralkylmercapto)-phenyl, (halo)-phenyl, (trifluoromethyD-phenyl,(nitro)-phenyl, (di-lower alkylamino)-phenyl, furyl, (lower alkyl)-furyl, thienyl, (lower alkyl) -thienyl, pyridyl or (loweralkyl)-pyridyl.

The compounds of the invention exhibit valuable pharmacologicalproperties. Apart from antibacterial, such as against Mycoplasmagallinarum, and growth promoting effects, they show a marked activityagainst parasites causing coccidiosis, such as Eimeria tenella,acervulina, adenoides, agridis, brunetti, hagam', maxima and necatrix.This can be demonstrated, for example, in in vitro or in vivo tests,using advantageously mammals or birds, e.g. mice or chickens, as testobjects. The coccidiostatic activity of the compounds of this inventioncan be estimated, for example, by the prophylactic or curative effect ofa standard feed containing between about 0.0001 and about 0.1%,preferably between about 0.01 to about 0.05% of said active compounds,fed to chickens 1 to 2 days prior or after their inoculation withsporulated oocysts of said Eimeria strains. Besides the above-mentionedutility, the compounds of this invention are also useful intermediatesin the manufacture of other valuable products, particularly ofpharmacologically active compounds.

Valuable compounds are those of Formula I, in which Am is di-loweralkylamino, lower alkyleneimino or monooxa-, monothiaor monoaza-loweralkyleneimino wherein 2 heteroatoms are separated by at least 2 carbonatoms, R, is hydrogen or lower alkyl, and each of R and R is phenyl,(lower alkyl)-phenyl, (lower alkoxy)-phenyl, (loweralkylmercapt-o)-phenyl, (halo)-pheny1, (trifluoromethyD-phenyl,(nitro)-phenyl, (di-lower alkylamino)- phenyl, furyl, (loweralkyl)-furyl, thienyl, (lower alkyl)- thienyl, pyridyl or (loweraIkyD-pyridyl.

Particularly useful are compounds of Formula II in which each of m and nis an integer from 1 to 4 and each of R and R is hydrogen or halogen.

Especially valuable are the compounds of Formula II, in which each of mand n is the integer 1 or 2, and each of R and R is hydrogen orchlorine.

The compounds of the invention are either prepared according to themethods known for the preparation of thiophene-Ll-dioxides oradvantageously according to the new method comprising the addition oflower alkynylamines to 2,3-diaryl-thiirene-1,1-dioxides, which may bedepicted as follows:

The above reactions are carried out according to standard methods, inthe presence or absence of diluents, preferably such as are inert to thereagents and are solvents thereof, of catalysts, condensing agentsand/or inert atmospheres, at low temperatures, room temperature oradvantageously elevated temperatures, at atmospheric or superatmosphericpressure.

The invention further includes any variant of the present process, inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of reactive derivatives orsalts thereof. Mainly, those starting materials should be used in theprocess of the invention that lead to the formation of those compoundsindicated above as being specially valuable.

The starting material used is known or, if new, may be preparedaccording to known methods, e.g. those described in Angew. Chem. 1967,p. 767 or J. Am. Chem. Soc. 87, 5804 (1965).

The compounds of the invention can be used, for example, in the form ofpharmaceutical or veterinary compositions, animal feedstuifs oradditives to feedstuffs, which are a further object of the presentinvention. The former contain said compounds in conjunction or admixturewith inorganic or organic, solid or liquid pharmaceutical excipientssuitable especially for enteral administration. Suitable excipients aresubstances that do not react with the compounds of the invention, forexample, water, gelatine, gums, sugars, e.g. lactose, glucose orsucrose, starches, e.g. corn starch or arrowroot, stearic acid or saltthereof, e.g. magnesium or calcium stearate, talc, alcohols, e.g.stearyl or benzyl alcohol, propylene glycol or polyalkylene glycols,alginic acid and other known medicinal excipients. The compositions maybe, for example, tablets or pills, e.g. micropills, or in liquid form assolutions, suspensions or emulsions. They may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure or buffers. They are prepared by conventional methods andcontain about 0.1 to 75%, more particularly, 1 to 50%, of the activeingredient.

The feedstufis and additives for feedstufis or for the drinking watercontain the compounds of the invention together with conventionalextenders, diluents and/ or nutrients, such as sucrose, glucose,molasses, fermentation residues, cornmeal, ground and rolled oats, wheatshorts and middlings, meat scrap, oil cake, soybean and fish meal,alfalfa, clover, grass clippings and the like, mineral supplements, suchas bone meal, calcium carbonate, iodized salt and the like, vitamins,such as vitamins A, B, C and D, and other suitable substances, such aspreservants, e.g. benzoic acid. They contain the compounds of theinvention in an amount ranging between about 0.0001 and 0.1%, preferablybetween about 0.1 and 0.05%, whereas the additives may contain the puresubstances, when used, for example, for the drinking water, but usuallycontain between about 1 and 75%, preferably 1 and 50%, thereof. Theamount of the compounds of the invention administered via the veterinarycompositions or the drinking water corresponds to that given with themedicated feedstufis shown above. The veterinary compositions,feedstuffs and additives may contain one or more than one of othertherapeutically valuable substances, for example, sulfonamides,especially N-(6-chloro-2-pyrazinyl)-sulfanilamide, orN'-(Z-quinoxalinyl)-sulfanilamide, but alsoN'-(2,6-dimethoxy-4-pyrimidyl)-sulfanilamide,N'-(5-ethyl-1,3,4-thiadiazol-2-yl)-sulfanilamide, N-( methyl-3-isoxazolyl)-sulfanilamide, N'-(6-methoxy-3-pyridazinyl)- sulfanilamideand the N'-acetyl derivative thereof, N'-(4-methyl-2-pyrimidinyl)-sulfanilamide, N'-(2,6-dimethyl-4-pyrimidinyl)-sulfanilamide, N'-(5-methyl-1,3,4-thiadiazol-2-yl)-sulfanilamide, N'-('6-chloro-3-pyridazinyl)-sulfanilamide and thesodium salt thereof, N'-(2-phenyl-3-pyrazolyl)-sulfan.ilamide, N'-(2phenyl-5-methyl-3-pyrazo1yl)- sulfanilamide and the like, arsenicderivatives, e.g. 3-nitro- 4-hydroxyphenyl-arsonic acid or arsanilicacid, antibiotics, such as penicillin, e.g. procaine penicillin,streptomycin, aureomcyin, terramycin, tetracyclines, e.g.oxytetracycline, or chlortetracycline, bacitracines, e.g. zinc ormanganese bacitracin or bacitracin methylene disalicylate, antiparasiticagents, e.g. methyl-4-acetamino-2-ethoxy-benzoate,Z-amino-S-nitrothiazole,1-(S-nitrothiazolyl-Z)-2-oxo-tetrahydroimidazole, 6,7dialkoxy-4-hydroxy-3-quinolinecarboxylic acids or their lower alkylesters and/or tranquilizers, such as reserpine, methyll8-epi-O-me-thyl-reserpate, meprobamate and the like, and/or a compoundof US. Pat. No. 3,385,857.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade, and all parts wherever given are parts by weight.

Example 1 melting at 108-110.

Example 2 Feed additive containing 15% of the active ingredient.

Formula: Kg. 3-diethylamino 2,5 diphenyl 4 methyl-thicphene-l,1-dioxideSoybean lecithin 10 Soybean oil 10 Corn gluten feed 830 Procedure: Thecorn gluten feed is ground in a mill and passed through a sieve with0.85 mm. openings. 150 kg. thereof is mixed with the active ingredientand the premix obtained passed through a sieve with 0.85 mm. openings.The licithin and oil are mixed and added to the remainder corn glutenfeed, followed by the premix and the whole is blended and mixed for atleast 20 minutes.

Example 3 To a mixture of 10.0 g. of 2,3-di-p-chlorophenylthiirene-1,1-dioxide and 50 ml. benzene is added a solution of 4.0 g. ofdiethylpropynylamine in 10 ml. of benzene over a period of 10 minutes atroom temperature while stirring in an inert atmosphere. Hereupon thetemperature is allowed to rise to about 50 where the mixture isintermittently cooled and then stirred overnight at room temperature. Itis evaporated in vacuo, the residue triturated with diethyl ether andthe crystals formed are filtered cold. The solids are recrystallizedfrom diethyl ether to afford the 3-diethy1- amino 2,5 di p chlorophenyl4 methyl-thiophene- 1,1-dioxide of the formula melting at 119-120".

We claim: 1. A 3-amino-2,4-diaryl-thiophene-1,l dioxide of the formula RI Am Bl ills s l! wherein Am is diloweralkylamino, R is hydrogen orlower alkyl, and each of R and R is phenyl or phenyl substituted bylower alkyl, lower alkoxy, lower alkylmercapto, halo, trifluoro-methyl,nitro or diloweralkylamino.

2. A compound as claimed in claim 1 and having the formula R4 I R5 inwhich each of m and n is an integer from 1 to 4 and each of R and R ishydrogen or halogen.

3. A compound as claimed in claim 2 and being the 3- diethylamino 2,5diphenyl 4 methyl-thiophene-1,1- dioxide.

4. A compound as claimed in claim 2 and being the 3- diethylamino 2,5 dip chlorophenyl 4 methylthiophene-1,1-dioxide.

5. The process for the preparation of a 3-amino-2,4-diaryl-thiophene-l,l-dioxide of the formula;

R1 Am Bl i 1 l(Ill-Am Il -C to a 2,3-diary1-thiirene-1,l-dioxide of theformula RZ-C=CRB wherein Am, R R and R are as defined above.

No references cited.

HENRY R. JILES, Primary Examiner C. M. JAISLE, Assistant Examiner US.Cl. X.R.

260243 B, 247.1, 268 FT, 293.67, 293.68, 326.3, 326.55 M, 326.82, 294.8D; 424246, 248, 250, 263, 267, 274, 275

